The systematic investigations concerning stereoisomeric alicyclic β-amino acids [F. Fülöp, Chem. Rev. 101, 2181-2204 (2001)] were considered for a long time as having only theoretical interest but about in the last decade it has turned out that several representatives of these compounds can be found in nature and have per se remarkable pharmacological effects and, resp., they are building elements of biologically active more complex compounds. The alicyclic β-amino acids play an important role even in the preparation of modified (“non-natural”) analogues of biologically active peptides, and by changing the α-amino acids to β-amino acids it is possible to modify the effect of the peptide and/or its stability can be increased.
Due to the occurrence in nature of the alicyclic β-amino acids and such acids of other types as well as the valuable biological activity of their derivatives and their manifold synthetic useability, several novel enantioselective processes have been elaborated for their synthesis [F. Fülöp, Chem. Rev. 101, 2181-2204 (2001); F. Fülöp, T. A. Martinek and G. K. Tóth, Chem. Soc. Rev. 35, 323-334 (2006)]. This can be followed in the preparation of β-amino acid enantiomers and their use of ever increasing degree in asymmetric reactions.
A novel direction in the preparation of chiral β-amino acids is the β-amino acid synthesis from chiral monoterpene derivatives [e.g. from (+)- and (−)-α-pinene, (+)-3-carene] [Z. Szakonyi, T. Martinek, A. Hetényi and F. Fülöp, Tetrahedron:Asymmetry, 11, 4571-4579 (2000); S. Gyónfalvi, Z. Szakonyi and F. Fülöp: Tetrahedron:Asymmetry, 14, 3965-3972 (2003)]. From the thus-obtained β-amino acid derivatives having monoterpene skeleton 1,3-heterocyclics of varied structures have been prepared [Z. Szakonyi, T. Martinek, A. Hetényi and F. Fülöp, Tetrahedron:Asymmetry, 11 4571-4579 (2000); S. Gyónfalvi, Z. Szakonyi and F. Fülöp, Tetrahedron:Asymmetry, 14, 3965-3972 (2003); Z. Szakonyi and F. Fülöp, Arkivoc, xiv, 225-232 (2003)].
It has been observed, however, that, due to the monoterpene skeleton wherein the amino group of the amino acid is attached to a tertiary carbon atom, the reactivity of the compounds in relation to the reactivity of the simpler alicyclic analogues is decreased in a high degree. However, by the suitable choice of the starting materials the amino group can be attached to the secondary carbon atom whereby the β-amino acid derivatives get normal reactivity, simultaneously preserving the enantiomeric purity secured by the natural monoterpene starting materials.
It is known that most of the cancer patients have to be treated with chemotherapeutical agents, too. However, the effectivity of the chemotherapy is strongly decreased by the appearance of resistance against cytostatica, especially the multidrug resistance (MDR) against chemotherapeutical drugs. The resistance against the anti-cancerous drugs is often transmitted by the expression of excessive degree of the membrane pump called P-glycoprotein (P-gp or MDR1), and this protein is coded by a gene called mdr1.
The P-gp is a member of the ABC superfamily. These transporters depending on ATP decrease the intracellular drug concentration below the cytotoxic levels, whereby the cytostatica become increasingly less effective and the toxic side-effects become increasingly stronger during the treatment, since the membrane pump transports the cytostatica from the intracellular space to the extracellular space. The strong decrease of the intracellular cytostaticum concentration during the treatment renders possible the survival and metastasis of the pathogenic tumour cells [E. Andicott et al., Ann. Rev. Bioch. 58, 137-171 (1989)].
Consequently, the surmounting of the multidrug resistance is extremely important since in this way numerous cancers and contagious illnesses can be successfully treated. Today no effective drug is known by the aid of which this aim could be attained in vivo.
The investigation of multidrug resistance gains ground in an increasingly wide sphere. A very promising method of surmounting MDR is to develop MDR-modulators which can inhibit the activity of the P-glycoprotein.